A Post-Antimicrobial Era

Clinical Article

November 26, 2015

Multi-drug resistance in common clinical pathogens is a growing challenge in healthcare. Resistant infections are more difficult to treat and take longer to resolve. Resistance is essentially due to selective pressure exerted by the widespread presence of antibiotics in the biosphere, together with the facilitated transfer of resistant organisms by healthcare workers and patients. The increasing frequency of infections resistant to first and second-line antimicrobials is attributed to the injudicious use of antibiotics within medicine, veterinary practice and agriculture. There are currently many barriers to reducing the inappropriate use of antibiotics at a primary care level. These include patient expectations, lack of patient awareness surrounding antibiotic resistance, as well as the perception by prescribers or patients that resistance is only a theoretical or minimal risk (Costelloe et al., 2010).

The problem is further compounded by the declining number of new antibacterial medicines entering clinical practice. Until very recently, no new classes of antibiotics had been discovered since 1987 (Boseley, 2013). This had implications of diseases evolving faster than the medicines to treat them were being developed. It is a race against time to develop new medicines against evolving “superbugs”, in addition to preserving the existing arsenal of antibiotics. This race against resistance has been met with a renewed promise of a novel antibiotic on the horizon, termed teixobactin, which shows no development of resistance in clinically relevant bacteria (Ling, et al. 2015). The research group responsible for this discovery proposed a novel path towards the development of antibiotics, providing the impetus for further research and investment.

England’s Chief Medical Officer, Dame Sally Davies, warns that antibiotic resistance poses “a catastrophic threat”, stating “If we don’t act now, any one of us could go into hospital in 20 years for minor surgery and die because of an ordinary infection that can’t be treated by antibiotics” (Boseley, 2013). If antibiotic resistance continues to rise unchecked there will be a decreased willingness to perform standard surgical procedures, such as joint replacement, which would have particularly serious consequences in a world with an ageing population. The pharmaceutical industry is not investing in research and development in this field primarily because of the short lifespan of antibiotics owing to resistance development and the lack of profitability. The cost-to-benefit ratio of developing an antibiotic intended for short-term treatment is less in comparison to developing a medicine for a chronic disease, such as the cholesterol-lowering class of statins.

Bacteria may possess a natural trait that makes it inherently resistant, such as glycocalyx of Pseudomonas that forms a protective membrane to antibiotic penetration. Alternatively, bacteria may acquire resistance through mutation of its genes or by horizontal transfer of resistant genes (Todar, 2009). Mechanisms of bacterial resistance include barriers to entry, formation of biofilms, or presence of efflux pumps, all of which inhibit intracellular penetration of the antibiotic. The therapeutic action of the antibiotic may be inhibited by bacterial enzymes, target-site modification or increased synthesis of the target. The efficacy and clinical value of antibiotics is urgently under threat due to growing resistance, illustrating the need for action to be taken.

Growing awareness of antibiotic resistance has led to increased surveillance of drug-resistant infections; changing of prescribing trends; and risk minimising strategies, such as the National Hand Hygiene Initiative. Initial rates of resistance to a new antibiotic are conventionally around 1% (Odonkor, Addo, 2011). However this rate increases alongside rising antibiotic use with the potential emergence of multi-drug resistant strains.

With around 19 million antibiotic prescriptions written in Australia every year we have one of the highest rates of antibiotic use in the world (Cooper, 2012). Our high reliance on antibiotics calls for enhanced monitoring of usage and resistance patterns. In April 2012, the Australian Government endorsed the formation of the Antimicrobial Resistance Standing Committee for the analysis and coordinated surveillance of antimicrobial resistance within the country (Cruickshank, 2013). The committee recommended national priorities on issues relating to antimicrobial resistance. The Australian Commission on Safety and Quality in Health Care, in collaboration with Commonwealth agencies and professional organisations, is implementing an infection prevention program which requires the mandatory accreditation of hospitals and health services (Cruickshank, 2013). The initiative addresses antibiotic resistance with aims to standardise surveillance definitions, establish a national hand hygiene initiative and antimicrobial stewardship programs, as well as provide education for clinicians. A national surveillance system to monitor antimicrobial resistance and an alert system to notify medical practitioners of resistance patterns was recognised as a matter of national importance (Cruickshank, 2013). Effective surveillance can lead to the development of therapeutic guidelines for rational antibiotic use, as well as the identification of priorities for public health action to reduce the impact of antimicrobial resistance.

Combatting antibiotic resistance in Australia requires a coordinated effort from government, health, and research sectors. The strategy is based on four principles: the use of vaccines to prevent infection, the discovery of new antimicrobial agents, the development of novel diagnostic tools, and the implementation of policies to reduce the spread of infection (Prasad et al., 2013). Pharmacists play a crucial role in regulating and promoting quality use of medicines. This includes educating patients to use antibiotics as prescribed, completing the full treatment course, discouraging the sharing of prescriptions or the use of leftover prescriptions for a different type of infection. Other health care workers can also help fight resistance by strengthening infection prevention and control within the hospital and community. Community pharmacists have significant opportunities to provide clinical interventions through symptomatic relief of infections with over the counter medications and advising patients on the futility of antibiotic use in treating common viral infections.

In the hospital setting pharmacist-directed antimicrobial stewardship programs have proliferated considerably in the past decade. Around 30-40% of hospitalised patients are prescribed antimicrobials during their hospital stay. Australian studies have shown rates of inappropriate antibiotic use in hospitals as high as 50% (Chen et al., 2010). Antimicrobial stewardship refers to the systematic and coordinated approach to antimicrobial management designed to improve clinical outcomes by promoting selection of the optimal antimicrobial with the most appropriate dose, duration of therapy and route of administration. Successful programs have minimised toxicity and adverse reactions, as well as limiting the selection of resistant strains of microbes. Evidence shows that this has reduced health care costs and patient morbidity and mortality (Duguid, Cruickshank, 2011). Pharmacists play an active role in the antimicrobial stewardship team by participating in the development and application of antimicrobial formularies and prescribing guidelines in view of local microbiology and antimicrobial susceptibility patterns (Duguid, Cruickshank, 2011). The role of the pharmacist extends from research and therapeutic drug monitoring to the bedside with the education and counselling of patients.

Rating as high priority internationally, antimicrobial resistance is widely recognised as a major threat to public health. There is no ‘magic cure’ in the fight against antimicrobial resistance, instead there needs to be global action to fill the discovery void into research and development of new antibacterial medications. Healthcare professionals at the frontline of this campaign have the responsibility to raise awareness and act in accordance with rational antibiotic prescribing to reduce the threat of growing resistance.